American Association for Cancer Research
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Supplementary Figure 5 from Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer

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posted on 2024-04-02, 07:20 authored by Hewitt Chang, Jaqueline Marquez, Brandon K. Chen, Daniel M. Kim, Michael L. Cheng, Eric V. Liu, Hai Yang, Li Zhang, Meenal Sinha, Alexander Cheung, Serena S. Kwek, Eric D. Chow, Mark Bridge, Rahul R. Aggarwal, Terence W. Friedlander, Eric J. Small, Mark Anderson, Lawrence Fong

Supplementary Figure 5: Effects of concomitant treatments during denosumab treatment Heatmaps summarizing log2 fold changes from statistical analysis of functional markers CD137, CD27, CD40, CD40L, CD71, CD95, CTLA-4, HLA-DR, ICOS, Ki-67, NKG2D, OX40, PD-1, PD-L1, PD-L2, TIGIT and TIM3 when comparing (A) patients that received only chemotherapy or chemotherapy and steroids with patients that did not receive chemotherapy or steroids at pretreatment timepoint 1 (TP1) and post-treatment timepoints 2 and 3 (TP2 and TP3); (B) patients received only steroids with patients that received only chemotherapy or chemotherapy and steroids at TP2 and TP3; (C) patients that received only steroids with patients that did not receive chemotherapy or steroids at TP2 and TP3. Each box in the heatmap represents a lymphocyte cluster that was labeled according to the nearest landmark node they connect to on the scaffold map and ordered by cell count abundance. The pseudocolor represents clusters that showed a significant difference (q<0.05) in the log2 fold change, with red being significantly higher, while blue being significantly lower in group 2 of the two comparison groups.


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Denosumab is a fully human mAb that binds receptor activator of NFκB ligand (RANKL). It is routinely administered to patients with cancer to reduce the incidence of new bone metastasis. RANK–RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity. However, these interactions also can regulate immune cells including dendritic cells and medullary thymic epithelial cells. Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in patients with cancer. Blood was collected from 23 patients with prostate cancer and 3 patients with renal cell carcinoma, all of whom had advanced disease and were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T-cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of natural killer cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatments, can lead to the induction of immunologic checkpoints.See related Spotlight by Nasrollahi and Davar, p. 383.

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